Prostate cancer is the second leading cause of cancer death of American men. Metastatic prostate cancer is considered essentially incurable. In marked contrast, thyroid cancers can be effectively treated and, at times, cured even when widespread metastasis is present, because of the ability of the cells to concentrate iodine, making therapy with radioactive iodine possible and effective. The studies described in this proposal are aimed at transferring the gene for the thyroidal sodium-iodide symporter (NIS), the structure that is responsible for iodide trapping by thyroid cells, into prostate cancer cells, which will allow therapy with radioactive iodine. In addition, the potential role of this transfer as a means of gene therapy for metastatic prostate cancer is examined. The studies involve targeting expression of the NIS gene using prostate specific promoters in order to achieve prostate specific gene expression. The experiments we completed, in the previous SPORE funding period demonstrated the feasibility of NIS gene transfer in vitro and in vivo, and a phase I clinical trial will soon be opened of this novel genetically targeted radiotherapy for men with locally recurrent prostate cancer. The experiments outlined in renewal proposal will 1) complete the phase I trial and examine its results;2) bring to clinical trial a second generation adenovirus that through inclusion of a probasin promoter driving NIS expression is highly prostate specific;and 3) develop replicating adenovirus vectors that express NIS that will offer higher efficacy and specificity towards prostate cancer as well as increased activity after systemic administration, thereby targeting metastatic disease. These studies will serve to examine the potential of NIS gene transfer to prostate cancer as a method of therapy of metastatic disease and are the first so described. In addition, successful demonstration of radioiodine effect in our prostate cancer model will serve to stimulate interest in NIS as a therapeutic gene for other cancer types.